The present invention relates generally to cell lines and cell cultures, and models thereof, and more specifically to selection systems.
Protein-based therapeutic products have contributed immensely to healthcare and constitute a large and growing percentage of the total pharmaceutical market. Therapeutic proteins first entered the market less than 20 years ago and have already grown to encompass 10-30% of the total US market for pharmaceuticals. The trend towards therapeutic proteins is accelerating. In recent years, more than half of the new molecular entities to receive FDA approval were biologics produced mostly in mammalian cell systems, and an estimated 700 or more protein-based therapeutics are at various stages of clinical development, with 150 to 200 in late-stage trials.
Over the past two decades, substantial progress has been made to overcome some of the key barriers to large-scale mammalian cell culture, including improvements in vector design, host cell engineering, medium development, screening methods and process engineering, resulting in yield improvements of up to 100-fold over titers seen in the mid 1980's. Despite these improvements, developing new biopharmaceutical products remains an expensive and lengthy process, typically taking six years from pre-clinical process development to product launch, where 20-30% of the total cost is associated with process development and clinical manufacturing. Production costs by mammalian cell culture remain high, and new methods to provide a more effective approach to optimize overall process development are of highest interest to the industry, particularly as regulatory constraints on development timelines remain stringent and production demands for new therapeutics are rapidly rising, especially for the quantities required for treatment of chronic diseases. Production costs are a major concern for management planning, especially with intense product competition, patent expirations, introduction of second-generation therapeutics and accompanying price pressure, and pricing constraints imposed by regulators and reimbursement agencies. Reducing the cost of therapeutic protein development and manufacturing would do much to ensure that the next generation of medicines can be created in amounts large enough to meet patients' needs, and at a price low enough that patients can afford.
Traditionally, mammalian cells are engineered to express a desired product. Among the methods used to engineer such cells, selectable markers are generally used to ensure the selection of cells that express a desired product and, in some cases, amplify the copy number of the nucleic acid encoding the product to increase production. However, to date only a limited number of selectable markers, such as dihydroflate reductase or glutamine synthetase, have been found general use in mammalian cells. It is therefore desirable to identify additional selectable markers for genetic engineering of mammalian cells for production of biologics or other desired products.
Thus, there exists a need to provide selectable markers for engineering expression in mammalian cells of desired products such as biologics. The present invention satisfies this need and provides related advantages as well.